Anesthetics are drugs which produce anesthesia, a condition characterized by the inability to appreciate sensation. Two types of anesthesia are generally recognized: local anesthesia and general anesthesia. In local anesthesia, the anesthesia is confined to a portion of the body, whereas in general anesthesia, the anesthesia extends to the entire body.
Local anesthetics reversibly block impulse conduction in peripheral nervous tissue, thereby producing a transient loss of sensation in a circumscribed area of the body without causing a general loss of consciousness. This action can be used to block pain sensation to a specific area of the body. Hence, local anesthetics are used to prevent pain in surgical procedures, dental manipulations, injury and disease.
Lidocaine is a local anesthetic which may be applied topically, for example, to mucous tissues. However, its effectiveness as a topical anesthetic is limited by its low adsorption rate (via passive diffusion) through the skin; the salts of lidocaine do not diffuse through intact skin to any appreciable degree, whereas the base forms of lidocaine diffuse through intact skin only to a limited degree.
The hydrochloride salt form of lidocaine (lidocaine HCl) is also widely used as a local anesthetic and is normally administered via injection. However, systemic absorption of lidocaine can lead to adverse side effects such as drowsiness, confusion, nausea, seizures and coma. These side effects are aggravated by the vasodilating effect of lidocaine, which increases the rate of its absorption into the systemic blood circulation.
Systemic absorption can be reduced by the addition of a vasoconstrictor. For example, the presence of epinephrine helps retard adsorption of lidocaine, thereby reducing its systemic toxicity. Epinephrine has other desirable effects as well. For example, it may be desirable to increase the duration of the drug's local anesthetic effect. The duration of action of lidocaine, as with any local anesthetic, is proportional to the time during which it is in actual contact with nerve tissues. The vasoconstrictive effect of epinephrine maintains localization of lidocaine at the nerve thereby prolonging the drug's anesthetic effect, increasing the duration of action of lidocaine, as well as increasing its efficiency by decreasing the volume of solution required to achieve an anesthetic effect. In addition to reducing the systemic absorption of lidocaine, epinephrine acts to reduce bleeding at the site of the (i.e., subsequent) surgical procedure.
However, epinephrine is difficult to work with as it is rapidly degraded in the presence of oxygen (U.S. Pat. No. 5,334,138). Moreover, the addition of epinephrine to hydrochloric solutions of lidocaine reduces the storage stability of the anesthetic solution (WO 91111182).
In addition to problems associated with the side effects of lidocaine, local injection of the drug can be painful, particularly in sensitive areas of the body such as the face.
Although iontophoresis has been used as a painless and effective method to deliver lidocaine into the skin (Comeau et al., Arch Otolaryngol 98:114-120 (1973)), as with administration by injection, removal of lidocaine by the vasculature and subsequent systemic adsorption can result in toxic side effects. Although the use of vasoconstrictors to reduce adsorption of iontophoretically delivered drugs has been suggested, instability of epinephrine remains problematic (U.S. Pat. No. 5,334,138).
Thus, a need exists for stabilized formulations of lidocaine as well as non-invasive, convenient means of administering lidocaine which result in increased localized anesthetic effect of the drug.